Pulmonary hypertension (PH) is a disease characterized by high blood pressure in lung vasculature, including pulmonary arteries, pulmonary veins, and pulmonary capillaries. In general, PH is defined as a mean pulmonary arterial (PA) pressure ≥25 mm Hg at rest or ≥30 mm Hg with exercise. Hill et al., Respiratory Care 54(7):958-68 (2009). The main PH symptom is difficulty in breathing or shortness of breath, and other symptoms include fatigue, dizziness, fainting, peripheral edema (swelling in foot, legs or ankles), bluish lips and skin, chest pain, angina pectoris, light-headedness during exercise, non-productive cough, racing pulse and palpitations. PH can be a severe disease causing heart failure, which is one of the most common causes of death in people who have pulmonary hypertension Postoperative pulmonary hypertension may complicate many types of surgeries or procedures, and present a challenge associated with a high mortality.
PH may be grouped based on different manifestations of the disease sharing similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic approaches. Simonneau et al., JACC 54(1):S44-54 (2009). Clinical classification of PH was first proposed in 1973, and a recent updated clinical classification was endorsed by the World Health Organization (WHO) in 2008. According to the updated PH clinical classification, there are five main groups of PH: pulmonary arterial hypertension (PAH), characterized by a PA wedge pressure ≤15 mm Hg; PH owing to a left heart disease (also known as pulmonary venous hypertension or congestive heart failure), characterized by a PA wedge pressure >15 mm Hg; PH owing to lung diseases and/or hypoxia; chronic thromboemboli PH; and PH with unclear or multifactorial etiologies. Simonneau et al., JACC 54(1):S44-54 (2009); Hill et al., Respiratory Care 54(7):958-68 (2009). PAH is further classified into idiopathic PAH (IPAH), a sporadic disease in which there is neither a family history of PAH nor an identified risk factor; heritable PAH; PAH induced by drugs and toxins; PAH associated with connective tissue diseases, HIV infection, portal hypertension, congenital heart diseases, schistosomiasis, and chronic hemolytic anemia; and persistent PH of newborns. Simonneau et al., JACC 54(1):S44-54 (2009). Diagnosis of various types of PH requires a series of tests.
PH treatment depends greatly on the cause or classification of the PH. Where PH is caused by a known medicine or medical condition, it is known as a secondary PH, and its treatment is usually directed at the underlying disease. Treatment of pulmonary venous hypertension generally involves optimizing left ventricular function by administering diuretics, beta blockers, and ACE inhibitors, or repairing or replacing a mitral valve or aortic valve. PAH therapies include pulmonary vasodilators, digoxin, diuretics, anticoagulants, and oxygen therapy. Pulmonary vasodilators target different pathways, including prostacyclin pathway (e.g., prostacyclins, including intravenous epoprostenol, subcutaneous or intravenous treprostinil, and inhaled iloprost), nitric oxide pathway (e.g., phosphodiesterase-5 inhibitors, including sildenafil and tadalafil), and endotheline-1 pathway (e.g., endothelin receptor antagonists, including oral bosentan and oral ambrisentan). Humbert, M. Am. J. Respir. Crit. Care Med. 179:650-6 (2009); Hill et al., Respiratory Care 54(7):958-68 (2009). However, the current treatments provide no cure for the devastating PAH. Humbert, M. Am. J Respir. Crit. Care Med 179:650-6 (2009).
P2Y12 receptor is a G-protein-coupled membrane-bound receptor that is selectively activated by adenine nucleotides, and expressed in platelets, microglia and neuronal tissues. Von Kügelgen, I. Pharmacology of mammalian P2X- and P2Y-receptors, in BIOTREND Reviews, No. 3 (9-2008). P2Y12 receptor antagonists found to inhibit platelet aggregation include indirect, irreversible inhibitors such as thienopyridine prodrugs (e.g., ticlopidine, clopidogrel, and prasugrel), and direct, reversible inhibitors such as cangrelor (AR-C699311MX), ticagrelor (AZD6140), AR-C67085, and elinogrel (PRT-060128). Wallentin, L., Eur. Heart J. 30: 1964-77 (2009); Van Giezen, J. J. J. Eur. Heart J. Suppl. 1 10 (Suppl. D):D23-D29 (2008); Oestreich, J. H., Curr. Opin. Drugs 11(3):340-8 (2010).
Cangrelor is a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist. It reaches steady state concentrations in plasma within 30 min of start of infusion (bolus 30 μg/kg and infusion 4 μg/kg/min), and is rapidly cleared from plasma with a short half-life of 3-6 min. Wallentin, L., Eur. Heart J. 30: 1964-77 (2009); Harrington et al., N. Engl. J. Med. 361:2318-29 (2009); Bhatt et al., N. Engl. J. Med. 361:2330-41 (2009).
P2Y12 receptor is also expressed in vascular smooth muscle cells. Preclinical studies suggest that reversible P2Y12 inhibition may be associated with beneficial effects on P2Y12-mediated vasoconstriction, which effects may permit reduction in thrombogenic vasospasm or reduce deficits in myocardial perfusion after thrombsis. Husted & van Giezen, Cardiovascular Therapeutic 27:259-74 (2009). In particular, treatment with cangrelor or ticagrelor in a dog thrombosis model resulted in decreased reocclusion and cyclic flow variation, and improved myocardial flow compared with placebo in animals receiving tissue-type plasminogen activator and heparin after thrombus formation, Husted & van Giezen, Cardiovascular Therapeutic 27:259-74 (2009). However, no therapeutic effects of P2Y12 reversible antagonists have been reported on pulmonary hypertension, especially in the absence of thrombus formation.
Therefore, there remains a need for additional or alternative therapies for treating, preventing and delaying pulmonary hypertension, especially potent agents with fast onset and fast offset of action.